The present invention relates to hydroxylated aromatic and heteroaromatic derivatives which have HIV integrase inhibitory properties that have been characterized by specific structural and physicochemical features. This inhibitory property may be advantageously used, for example, to provide medicinals (e.g. compositions) with antiviral properties against HIV viruses, including the HIV-1 and HIV-2 viruses, i.e. the hydroxyphenyl derivatives including pharmaceutical compositions thereof may be used to inhibit the activity of HIV integrase.
The HIV (human immunodeficiency virus) retrovirus is the causative agent for AIDS (acquired immunodeficiency syndrome). Thus the HIV-1 retrovirus primarily uses the CD4 receptor (a 58 kDa transmembrane protein) to gain entry into cells, through high-affinity interactions between the viral envelope glycoprotein (gp 120) and a specific region of the CD4 molecule found in CD4 (+) T-helper lymphocytes and certain other cells (Lasky L. A. et al., Cell vol. 50, p. 975-985 (1987)). HIV infection is characterized by a period immediately following infection called xe2x80x9casymptomaticxe2x80x9d which is devoid of clinical manifestations in the patient. Progressive HIV-induced destruction of the immune system then leads to increased susceptibility to opportunistic infections, which eventually produces a syndrome called AIDS-related complex (ARC) characterized by symptoms such as persistent generalized lymphadenopathy, fever, weight loss, followed itself by full blown AIDS. After entry of the retrovirus into a cell, viral RNA is converted into DNA, which is then integrated into the host cell DNA. The reverse transcriptase encoded by the virus genome catalyzes the first of these reactions (Haseltine W. A. FASEB J. vol 5, p. 2349-2360 (1991)). At least three functions have been attributed to the reverse transcriptase: RNA-dependent DNA polymerase activity which catalyzes the synthesis of the minus strand DNA from viral RNA, ribonuclease H (RNase H) activity which cleaves the RNA template from RNA-DNA hybrids and DNA-dependent DNA polymerase activity which catalyzes the synthesis of a second DNA strand from the minus strand DNA template (Goff S. P. J. Acq. Imm. Defic. Syndr. Vol 3, p. 817-831 (1990)). At the end of reverse transcription, the viral genome now in the form of DNA (called provirus) is integrated into host genomic DNA and serves as a template for viral gene expression by the host transcription system, which leads eventually to virus replication (Roth et al., 1989). The preintegration complex consists of integrase, reverse transcriptase, p17 and proviral DNA (Bukrinsky M. I., Proc. Natn. Acad. Sci. USA vol. 89 p. 6580-6584 (1992)). The phosphorylated p17 protein plays a key role in targeting the preintegration complex into the nucleus of the host cell (Gallay et al., 1995).
The primary RNA transcripts made from the provirus are synthesized by the host cell RNA polymerase II which is modulated by two virus-encoded proteins called tat and rev. The viral proteins are formed as polyproteins.
Post-translational modifications of viral polyproteins include processing and glycosylation of Env (envelope) proteins, and myristylation of the N-terminal residue of the p17 protein in the Gag and Gag-Pol polyproteins. The viral protease is involved in processing polyproteins Gag and Gag-Pol into mature proteins, an essential step for virus infectivity. A number of synthetic antiviral agents have been designed to block various stages in the replication cycle of HIV. These agents include compounds which interfere with viral binding to CD4 (+) T-lymphocytes (for example, soluble CD4), compounds which block viral reverse transcriptase (for example, didanosine and zidovudine (AZT)), budding of virion from the cell (interferon), or the viral protease (for example Ritonavir and Indinavir). Some of these agents proved ineffective in clinical tests. Others, targeting primarily early stages of viral replication, have no effect on the production of infectious virions in chronically infected cells. Furthermore, administration of many of these agents in effective therapeutic doses has led to cell-toxicity and unwanted side effects, such as anemia, neurotoxicity and bone marrow suppression. Anti-protease compounds in their present form are typically large and complex molecules of peptidic nature that tend to exhibit poor bioavailability and are not generally consistent with oral administration. These compounds often exhibit side effects such as nausea, diarrhea, liver abnormalities and kidney stones. None of the known antiviral agents target the HIV integrase.
Accordingly, the need exists for compounds that can effectively inhibit the action of this viral enzyme and that can be used for treating HIV infections.
The terms HIV integrase and integrase as used herein are used interchangeably and refer to the integrase enzyme encoded by the human immunodeficiency virus type 1 or 2. In particular this term includes the human immunodeficiency virus type 1 integrase.
Thus, the present invention relates to a compound of formula Ixe2x80x2
and pharmaceutically acceptable derivatives thereof including, for example, where applicable or appropriate pharmaceutically acceptable salts thereof. Ar may, for example, be R1 which is referred to below; Arxe2x80x2 may, for example, be R2 which is also referred to below.
A compound in accordance with the present invention may, for example, take the form of a compound of formula IIxe2x80x2, IIIxe2x80x2 or IVxe2x80x2 below: 
In accordance with the present invention, n may be 1, 2 or 3; Hal may represent a halogen atom (e.g. Cl, Br, F or I); p may be 0, 1 or 2; X and Xxe2x80x2 may each independently represent a single bond, a saturated straight or branched hydrocarbon group of 1 to 4 carbon atoms, or a straight or branched hydrocarbon group of 2 to 4 carbon atoms comprising a carbon to carbon double bond; and W may represent an amino acid residue or fragment (in particular alpha-amino acid residues) such as for example a residue based on tyrosine, DOPA, hydroxyproline, serine, threonine, histidine, valine, phenylalanine, lysine, alanine, glycine, glutamic acid, aspartic acid, arginine, asparagine, glutamine, leucine, lysine, isoleucine, proline, tryptophan, methionine, cysteine, cystine, thyroxine, meta-tyrosine, sarcosine, other alpha-methyl amino acids such as alpha-methyl DOPA, as well as other 3-substituted tyrosines, and the like.
Za may, for example, be a substituent selected from H, NO2, NH2, alkyloxy, cycloalkyloxy, aryloxy (e.g. benzyloxy), SH, thioalkyl, thioaryl, NHCO-alkyl, NHCO-aryl, etc. Za may, for example, be referred to hereinafter interchangeably with respect to particular radicals, groups or moieties, etc. as R7, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, ect.
In accordance with the present invention an alkyl radical, group or moiety may signifiy an unsubstituted straight-chained (or branched alkyl group) with 1 to 8 carbon atoms; a cycloalkyloxy radical group or moiety may comprise 3 to 8 carbon atoms; an aryl radical, group or moiety may signify a phenyl (or benzyl) group which may be substituted by one or more (e.g. one to three), same or different, substituents such as for example OH, OCH3, SH, SCH3, NO2, NH2, F, Cl, and Br, etc.
Y and Yxe2x80x2 may, for example, each independently be C or N.
Ar and Arxe2x80x2 may, for example, each independently represent an aromatic radical, group or moiety which is incorporated into a compound of formula Ixe2x80x2 by using an appropriate amine, benzoyl hydrazide or carboxylic acid selected, for example, from the following commercially available or synthetic molecules; dopamine, benzylamine, 2,5-dimethoxyaniline, 3-hydroxy-4-methoxyaniline, thiazole-2-amine, 2-(2xe2x80x2-thiophenyl)ethylamine, benzoyl hydrazide, salicylic hydrazide, caffeic acid, dihydrocaffeic acid, 3,4-dihydroxybenzoic acid, 3,5-dihydroxynaphthalene-2-carboxylic acid, 4,8-dihydroxyquinoline-2-carboxylic acid, 2,4-dihydroxypyrimidine-5-carboxylic acid, 2,5-dimethoxycinnamoic acid, 3,4-di-(4-fluorobenzyloxy)benzoic acid, 3,4-di-(4-fluorobenzyloxy)caffeic acid, 5-fluoro-2-hydroxybenzoic acid, 5-fluoroindole-2-carboxylic acid, 2-fluoro-6-hydroxybenzoic acid, 3-hydroxy-4-nitrobenzoic acid, 4-hydroxy-3-nitrobenzoic acid, indole-2-carboxylic acid, N-(4-fluorobenzyl)indole-2-carboxylic acid, N-(4-fluorobenzyl)indole-2-carboxylic acid, 3-nitrocinnamoic acid, 4-nitrocinnamoic acid, pyrrole-2-carboxylic acid, trans-3-indole acrylic acid, 2,4,6-trihydroxybenzoic acid, 3,4,5-trihydroxybenzoic acid, 2-thiophene acetic acid, and the like.
W may, for example, be W1 which is referred to below. W may, for example, be derived from natural or unnatural alpha-amino acids. The term unnatural alpha-amino acid refers to alphaxe2x80x94amino acids which do not occur in nature but which can be derived from naturally occurring alphaxe2x80x94amino acids or other chemical reagents by methods known to those skilled in the art.
W may, for example, represent a group of formula 
wherein A represents a group of formula 
Ra (also referred to herein as R3) may represent H or xe2x80x94CH3; Rb (also referred to herein as R4) may represents H or xe2x80x94CH3; Rc (also referred to herein as R6) may represent H or OH; and R (also referred to herein as R5) may be selected from the group consisting of H, CH3xe2x80x94, (CH3)2CHxe2x80x94, (CH3)2CHCH2xe2x80x94, CH3CH2CH(CH3)xe2x80x94, C6H5CH2xe2x80x94, CH3SCH2CH2xe2x80x94, HO2CCH2xe2x80x94, H2NC(O)CH2xe2x80x94, HO2CCH2CH2xe2x80x94, H2NC(O)CH2CH2xe2x80x94, H2NCH2CH2CH2xe2x80x94, H2NCH2CH2CH2CH2xe2x80x94, H2NCH2CH2CH2CH2CH2xe2x80x94, HOCH2xe2x80x94, CH3CH(OH)xe2x80x94, HSCH2xe2x80x94
This invention also envisions the presence of a substituent on the side chain of an amino acid residue which bears a functional group such as an alcohol, a phenol, a thiol, a carboxylic acid, an amide, an imidazole, an indole, a pyrrolidine or a guanidine function. For example, the substituents on such functions (e.g. sometimes referred to herein as Rxe2x80x2 or R20) may be selected appropriately from Boc, Fmoc, Bzl, Z, tBu, cHx, Dnp, Trt, Mtt, etc., chosen according to the amino acid used.
Therefore, the present invention in particular provides derivatives wherein R (or R5) may be selected from the group consisting of Rxe2x80x2O2CCH2xe2x80x94, Rxe2x80x2HNC(O)CH2xe2x80x94, Rxe2x80x2O2CCH2CH2xe2x80x94, Rxe2x80x2HNC(O)CH2CH2xe2x80x94, Rxe2x80x2HNCH2CH2CH2xe2x80x94, Rxe2x80x2HNCH2CH2CH2CH2xe2x80x94, Rxe2x80x2HNCH2CH2CH2CH2CH2xe2x80x94, Rxe2x80x2OCH2xe2x80x94, CH3CH(ORxe2x80x2)xe2x80x94, Rxe2x80x2SCH2xe2x80x94
The present invention more particularly provides a compound of formula 
and pharmaceutically acceptable derivatives thereof including where applicable or appropriate pharmaceutically acceptable salts thereof, e.g. where applicable pharmaceutically acceptable salts, e.g. when a compound of formula I comprises a carboxylic acid group pharmaceutically acceptable salts thereof and when a compound of formula I comprises an amino group pharmaceutically acceptable ammonium salts thereof,
Wherein W1 represents a group of formula 
A represents a group of formula 
R1 represents a group of formula 
R2 represents a group of formula 
R3 represents H or xe2x80x94CH3, R4 represents H or xe2x80x94CH3, R6 represents H or OH,
R8 is hydrogen, unsubstituted benzyl, 4-fluorobenzyl or a substituted benzyl of formula R19C6H4CH2xe2x80x94
R5 is selected from the group consisting of Rd and Re, provided that when R1 is a group of formula III and R2 is a group of formula VIII, R5 is Re,
Rd being selected from the group consisting of H, C1 to C8 alkyl (straight or branched), HO2Cxe2x80x94(C1 to C8)alkyl (straight or branched)xe2x80x94, C6H5CH2xe2x80x94, CH3S CH2CH2xe2x80x94, H2NC(O)xe2x80x94(C1 to C8)alkyl (straight or branched)xe2x80x94, HO(C1 to C8)alkyl (straight or branched)xe2x80x94, HSCH2xe2x80x94, H2Nxe2x80x94(C1 to C8)alkyl (straight or branched), (e.g. such as CH3xe2x80x94, (CH3)2CHxe2x80x94, (CH3)2CHCH2xe2x80x94, C6H5CH2xe2x80x94, CH3CH2CH(CH3)xe2x80x94, CH3SCH2CH2xe2x80x94, HO2CCH2xe2x80x94, H2NC(O)CH2xe2x80x94, HO2CCH2CH2xe2x80x94, H2NC(O)CH2CH2CH2xe2x80x94, H2NCH2CH2CH2CH2xe2x80x94, H2NCH2CH2CH2CH2CH2xe2x80x94, HOCH2xe2x80x94, CH3CH(OH)xe2x80x94, HSCH2xe2x80x94) 
Re being selected from the group consisting of R20O2Cxe2x80x94(C1 to C8)alkyl (straight or branched)xe2x80x94, R20HNC(O)xe2x80x94(C1 to C8)alkyl (straight or branched)xe2x80x94, R20HNxe2x80x94(C1 to C8)alkyl (straight or branched), R20Oxe2x80x94(C1 to C8)alkyl (straight or branched)xe2x80x94, R20SCH2xe2x80x94 (e.g. such as, R20O2CCH2xe2x80x94, R20HNC(O)CH2xe2x80x94, R20O2CCH2CH2xe2x80x94, R20HNC(O)CH2CH2xe2x80x94, R20HNCH2CH2CH2xe2x80x94, R20HNCH2CH2CH2CH2xe2x80x94, R2OHNCH2CH2CH2CH2CH2xe2x80x94, R20OCH2xe2x80x94, CH3CH(OR20)xe2x80x94, R20SCH2xe2x80x94), 
R20 is a predetermined protecting group substitutent (i.e. chosen according to the substituent to be protected)
R7 and R15, are each independently selected from the group consisting of Hal, xe2x80x94NO2, xe2x80x94NH2, alkyl-Oxe2x80x94, cycloalkyl-Oxe2x80x94, aryl-Oxe2x80x94, benzyloxy, xe2x80x94SH, alkyl-Sxe2x80x94, aryl-Sxe2x80x94, alkyl-CONHxe2x80x94, aryl-CONH, wherein alkyl signifies an unsubstituted straight or branched alkyl group with 1 to 8 carbon atoms, cycloalkyl signifies an unsubstituted radical with 3 to 8 carbon atoms and aryl signifies an unsubstituted phenyl group, an unsubstituted benzyl group or a phenyl or benzyl group substituted by one or more (i.e. 1 to 3) of the same or different substituents selected from the group consisting of xe2x80x94OH, xe2x80x94OCH3, xe2x80x94SH, xe2x80x94SCH3, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94F, xe2x80x94Cl, and xe2x80x94Br,
R9, R10, R11, R12, R13, R14, R16, R17, R18, and R19, are each independently selected from the consisting of H, Hal, xe2x80x94NO2, xe2x80x94NH2, alkyl-Oxe2x80x94, cycloalkyl-Oxe2x80x94, aryl-Oxe2x80x94, benzyloxy, xe2x80x94SH, alkyl-Sxe2x80x94, aryl-Sxe2x80x94, alkyl-CONHxe2x80x94, aryl-CONH, wherein alkyl signifies an unsubstituted straight or branched alkyl group with 1 to 8 carbon atoms, cycloalkyl signifies an unsubstituted radical with 3 to 8 carbon atoms and aryl signifies an unsubstituted phenyl group, an unsubstituted benzyl group or a phenyl or benzyl group substituted by one or more (i.e. 1 to 3) of the same or different substituents selected from the group consisting of xe2x80x94OH, xe2x80x94OCH3, xe2x80x94SH, xe2x80x94SCH3, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94F, xe2x80x94Cl, and xe2x80x94Br, R21, R22 and R23 are each independently selected from the group consisting of H, alkyl, benzyl, wherein alkyl signifies an unsubstituted straight or branched alkyl group with 1 to 8 carbon atoms, unsubstituted benzyl group or benzyl group substituted by one or more (i.e. 1 to 3) of the same or different substituents selected from the group consisting of xe2x80x94OH, xe2x80x94OCH3, xe2x80x94SH, xe2x80x94SCH3, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94F, xe2x80x94Cl, and xe2x80x94Br,
Hal represents a halogen atom (F, Cl, Br, and I),
X and Xxe2x80x2 each independently represents a single bond, a saturated straight or branched hydrocarbon group of 1 to 4 carbon atoms (e.g. alkyl) or a straight or branched hydrocarbon group of 2 to 4 carbon atoms comprising a carbon to carbon double bond;
Y and Y1 each independently represents an atom selected from the group consisting of C, or N,
n is 1, 2 or 3, nn is 0, 1, 2 or 3, mm is 0 or 1, p is 0 , 1 or 2, o is 0 or 1 q is 0 or 1,
provided that for the group of formula III when Y and Y1 are each N, n is 1 or 2 and p is 0 or 1 and provided that when R1 is a group of formula III and R2 is a group of formula VIIIa, q cannot be 0 for the group of formula VIIIa.
It is to be understood herein that n and p are to be selected in relation to each other as well as in relation to the possible presence any other group(s) (e.g. R7) that may be present therewith (e.g. if n is 2 and R7 is H, p is 0, if both Y and Y1 are N; if n is 1 and R7 is H, p may be 1, if both Y and Y1 are C); similarly for o, nn, mm and q. Furthermore, in accordance with the present invention, for the groups of formula III when Y and Y1 are each N, n may be 1 or 2 and p may be 0 or 1.
In accordance with the present invention, R20 may be any suitable (known) predertermined protecting group substitutent, e.g. mono- or poly substituted benzyl protective groups, mono- or poly substituted benzyloxycarbonyl protective groups, mono- or poly substituted trityl protective groups, etc. . . . ; see T. W. Greene and P. G. M. Wuts, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d 3rd Ed. John Wiley and Sons (1999). R20 may, for example, be a predertermined protecting group substitutent selected from the group consisting of Boc (tert-butoxycarbonyl), Fmoc (9-fluorenylmethoxycarbonyl), Bzl (benzyl), Z (benzyloxycarbonyl), tBu (tert-butyl), cHx (cyclohexyl), Dnp (2,4-dinitrophenyl), Trt (trityl), Mtt (methyltrityl), p-Br-benzyl, p-Cl-benzyl, 2,6-dichlorobenzyl, 2,6-fluorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, 4-methylbenzyl, trifluoromethylbenzyl, p-acylamino-benzyl (e.g. the acyl moiety thereof may contain 1 to 8 carbon atoms in addition to the carbon atom of the carbonyl groupxe2x80x94for example alkyl (straight or branchedxe2x80x94saturated or unsaturated), cycloalkyl, etc.) p-azidobenzyl, 4-azido-3-chlorobenzyl, p-(methylsulfinyl)benzyl, 4,4xe2x80x2-dimethoxybenzhydryl, 2-bromobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, straight or branched C1-C8-alkyl, C3-C8-cycloalkyl, xanthyl, 4-methoxytrityl, di-(4-methoxy)trityl, and tri-(4-methoxy)trityl.
The present invention also contemplates a compound of formula I or Ixe2x80x2 as defined herein wherein said compound is optically active and where applicable pharmaceutically acceptable salts, amides and esters thereof.
The present invention further provides a pharmaceutical composition (e.g a composition for inhibiting the activity of HIV integrase) comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of at least one compound of formula I or Ixe2x80x2 as defined herein.
The present more particularly provides an hydroxyphenyl compound of formula Ia 
and where applicable pharmaceutically acceptable salts thereof wherein n, p, Hal, Xxe2x80x2, Y, Y1, R3, R5 and R7 are as defined herein and m is 1 or 2, and provided that, when Y and Y1 are each N, n is 1 or 2 and p is 0 or 1. In accordance with the present invention, for a hydroxyphenyl compound of formula Ia as defined above Y and Y1 may each be C, p may be 0, and R7 may be NO2xe2x80x94 or NH2xe2x80x94; Xxe2x80x2 may be selected from the group consisting of a single bond, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94 and xe2x80x94CH2CH2xe2x80x94; R3 may be H; etc.
The present invention further provides an hydroxyphenyl compound of formula Ib 
wherein R2 represents a group of formula VIIIa 
and wherein nn is 1, 2 or 3, and Y, X, R8 and R15 are as defined herein.
In accordance with the present invention, for an hydroxyphenyl compound of formula Ib as defined above R2 may represent a group of formula 
wherein m is 1 or 2; for a compound of formula Ia R3 may be H.
The present invention further provides a hydrazide compound of formula Ic 
wherein R2 represents a group of formula IX 
and wherein n, R1, R3, R5, R8 and R16 are as defined herein. In accordance with the present invention, for a hydrazide compound of formula Ic as defined above, R2 may represent a group of formula 
In accordance with the present invention for a hydrazide compound of formula Ic as defined above, R1 may be a group of formula III as defined herein, p may be 0, n may be 1 or 2, Y may be C and Y1 may be C; R1 may be a group of formula IV as defined herein and may be H; R1 may be a group of formula VIa as defined herein, R12 may be H, and o may be 0.
The present invention also provides a compound of formula Id 
wherein R2 represents a group of formula VIIIa 
wherein nn is 1, 2or 3, q is 1, and R1, R3, R5, R8 and R15 are as defined herein. In accordance with the present invention for a compound of formula Id as defined above R2 may represent a group of formula 
R1 may be a group of formula III, IIIa, V, or VI as defined herein, n may be 1 or 2, p may be 0 or 1, Hal may be F; for a compound of formula Id as defined herein R2 may, for example, alternatively represent a group of formula 
wherein R1 may be a group of formula III, IIIa, V, or VI as defined herein, n may be 1 or 2, p may be 0 or 1, Hal may be F.
The present invention additionally provides a thiazole-2-amine compound of formula Ie 
wherein R2 represents a group of formula X 
wherein o, q, R1, R3, R5, R8, and R17 are as defined herein. In accordance with the present invention for a thiazole-2-amine compound of formula Ie as defined above R2 may represent a group of formula 
R1 may be a group of formula III, IIIa, V, or VI as defined herein, n may be 1 or 2, p may be 0 or 1, Hal may be F.
The present invention furthermore provides a thiophene compound of formula If 
wherein R2 represents a group of formula XI 
and wherein mm, q, R1, R3, R5, R8, and R18 are as defined herein. In accordance with the present invention for a thiophene compound of formula If as defined above wherein R2 may represent a group of formula 
R1 may be a group of formula III, IIIa, V, or VI as defined herein, n may be 1 or 2, p may be 0 or 1, Hal may be F.
In accordance with the present invention there is further provided an hydroxyphenyl compound of formula Ig 
and where applicable pharmaceutically acceptable salts thereof, wherein n is 1, 2 or 3, p, Hal, Xxe2x80x2, Y, Y1, R3, R5 and R7 are as defined herein, m is 1 or 2 and provided that, when Y and Y1 are each N, n is 1 or 2 and p is 0 or 1. In accordance with the I; present invention for an hydroxyphenyl compound of formula Ig as defined above wherein Y and Y1 may each be C, p may be 0, R7 may be NO2xe2x80x94 or NH2xe2x80x94; Xxe2x80x2 may be selected from the group consisting of a single bond, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94 and xe2x80x94CH2CH2xe2x80x94; R3 may be H.
The present invention also provides an hydroxyaryl compound of formula II 
and pharmaceutically acceptable derivatives thereof including where applicable or appropriate pharmaceutically acceptable salts thereof, wherein n is 1, 2 or 3, p is 0, 1 or 2, Hal, X, Xxe2x80x2, Y, Y1, R3, Re and R4 are as defined herein; for the compound of formula II R20 may be a predertermined protecting group substitutent selected from the group consisting of Boc (tert-butoxycarbonyl), Fmoc (9-fluorenylmethoxycarbonyl), Bzl (benzyl), Z (benzyloxycarbonyl), tBu (tert-butyl), cHx (cyclohexyl), Dnp (2,4-dinitrophenyl), Trt (trityl), Mtt (methyltrityl). Xxe2x80x2 may for 5 example be a single bond, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94 or xe2x80x94CH2CH2xe2x80x94. The compound of formula II may have an optical structure similar to that shown above for the compound of formula Ig.
As mentioned, the present invention include pharmaceutically acceptable derivatives of the compound of formula I or Ixe2x80x2 (e.g. IIxe2x80x2, IIIxe2x80x2, etc.). As used herein the expression xe2x80x9cpharmaceutically acceptable derivativexe2x80x9d is to be understood as referring to any pharmaceutically acceptable salt, amide, ester, or salt of such ester, of a compound of this invention.
The present invention provides, where appropriate, salts (e.g. derived from appropriate bases or acids) which include but are not limited to alkali metal (e.g., sodium, potassium, cesium, etc.) salts, alkaline earth metal (e.g., magnesium) salts, and ammonium salts such as acid addition salts of amines (e.g. ammonium chloride salts) as well as quaternary ammonium salts of for example Nxe2x80x94(Rxe2x80x3)4+ type wherein Rxe2x80x3 is an organic residue.
The pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of such acid salts include: acetate adipate, alginate aspartate benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylhydrogensulfate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycollate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthylsulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, perchlorate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate, and undecanoate.
This invention also envisions the quaternization of any basic nitrogen containing groups of the compounds disclosed herein. The basic nitrogen can be quaternized with any agents known to those of ordinary skill in the art including, for example, lower alkyl halides, such as methyl, ethyl, propyl and butyl chloride, bromides and iodides; dialkyl sulfates including dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodide; and arylalkyl halides including benzyl and phenethyl bromides. Water or oil-soluble or dispersible products may be obtained by such quaternization.
In any event, it is also to be understood that for the present invention the expression xe2x80x9cpharmaceutically acceptable derivativexe2x80x9d is to be understood as referring to any other compound having a structure such that, upon administration to a recipient, it is capable of providing (directly or indirectly) a compound of this invention or an antivirally active metabolite or residue thereof. Thus the compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral bioavailability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
The present invention in particular provides a dopamine or benzylamine derivative selected from the group consisting of a compound of formula IA 
and where applicable pharmaceutically acceptable salts thereof wherein n, p, Hal, Xxe2x80x2, Y, Y1, Za, Ra and R are as defined herein.
The present invention in particular provides a dopamine or benzylamine derivative selected from the group consisting of a compound of formula IIA 
wherein n, Y, Ra and R are as defined above.
The present invention in particular provides a salicylic hydrazide derivative selected from the group consisting of a compound of formula IIIA 
wherein Ar, Ra and R are as defined above.
The present invention in particular provides a 2,5-dimethoxyaniline derivative selected from the group consisting of a compound of formula IVA 
wherein Ar, Ra and R are as defined above.
The present invention in particular provides a thiazole-2-amine derivative selected from the group consisting of a compound of formula IVAA 
wherein Ar, Ra and R are as defined above.
The present invention in particular provides a 2-(2xe2x80x2-thiophene)ethylamine derivative selected from the group consisting of a compound of formula IVAAA 
wherein Ar, Ra and R are as defined above.
The compounds of this invention contain one or more asymmetric carbon atoms and thus may occur as racemates and racemic mixtures, single enantiomer, diastereomeric mixtures and individual diastereoisomers. All such isomeric forms of these compounds are expressly included in the present invention. Each stereogenic carbon may be of the R or S configuration.
The amino acid residues may, for example, in any event, be of L, D or DL form, preferably of L form; thus for example the amino acid residue (i.e. W) may be a L-xcex1-amino residue, a D-xcex1-amino residue, or a DL-xcex1-amino residue.
Accordingly, the present invention further provides a dopamine or benzylamine derivative selected from the group consisting of a compound of formula IB 
and where applicable pharmaceutically acceptable salts, thereof, wherein n is 1, 2 or 3, p, Hal, Xxe2x80x2, Y, Y1, Za, Ra and R are as defined above.
In the same way or fashion, optically active compounds are envisioned for other compound structures of the present invention, e.g. for derivatives possessing formula IIA, IIIA, IVA, IVAA and IVAAA.
The compounds of the present invention including where applicable their pharmaceutically acceptable derivatives have an affinity for integrase, in particular, HIV integrase. Therefore, these compounds are useful as inhibitors of such integrase, i.e. they are in particular useful as HIV integrase inhibitors. These compounds can be used alone or in combination with other therapeutic or prophylactic agents, such as antivirals, antibiotics, immunomodulators or vaccines, for the treatment or prophylaxis of viral infection.
According to the present invention, the compounds of this invention are capable of inhibiting HIV viral replication in human CD4+ T-cells, by inhibiting the ability of HIV integrase to integrate the double stranded DNA into host genomic DNA for further virus replication by the host cell machinery (Sakai H., J. Virol. Vol. 67 p. 1169-1174 (1993)). These novel compounds can thus serve to reduce the production of infectious virions from acutely infected cells, and can inhibit the initial or further infection of host cells. Accordingly, these compounds are useful as therapeutic and prophylactic agents to treat or prevent infection by HIV-1 and related viruses, which may result in asymptomatic HIV-1 infection, AIDS-related complex (ARC), acquired immunodeficiency syndrome (AIDS), AIDS-related dementia, or similar diseases of the immune system.
Thus the present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of at least one hydroxyphenyl derivative as defined above. The pharmaceutical compositions may be used to inhibit integrase, including HIV integrase, thus providing protection against HIV infection.
The expression xe2x80x9cpharmaceutically effective amountxe2x80x9d is to be understood herein as referring to an amount effective in treating HIV infection in a patient. The term prophylactically effective amount refers to an amount effective in preventing HIV infection in a patient. As used herein, the term patient refers to a mammal, including a human. The expressions xe2x80x9cpharmaceutically acceptable carrierxe2x80x9d (or adjuvant) and xe2x80x9cphysiologically acceptable vehiclexe2x80x9d are to be understood as referring to a non-toxic carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof. These factors will be discussed in more detail below.
The compounds of this invention may be readily prepared using conventional techniques from commercially available and cheap starting materials. The relative ease of synthesis of the products described in this invention represents a marked advantage for the large scale preparation of these compounds. In general, the derivatives of the present invention may be readily obtained from amino acids through sequences recognized by those knowledgeable in the art as straightforward, requiring readily available reagents and easy techniques. Using standard techniques, amino acids may be transformed to the desired HIV integrase inhibitors according to approaches as shown in Scheme 1, Scheme 2, Scheme 3, Scheme 4, and Scheme 5 which are discussed below. Scheme 6 shows the preparation of two non commercial aromatic acids derived from pyrrole-2-carboxylic acid and indole-2-carboxylic acid which are used in the preparation of HIV integrase inhibitors.
Scheme 1 illustrates a generic example for the preparation of a derivative in accordance with the present invention:
Note:
a) For scheme 1, PG and PGxe2x80x2 may be any suitable (known) independently removable protecting group for respectively protecting the amine functional group and the amino acid side chain functional group, when necessary. PG may, for example, be Boc i.e. tert-butoxycarbonyl or Fmoc i.e. 9-fluorenylmethoxycarbonyl and PGxe2x80x2 may, for example, be tert-Butyl, Boc, Fmoc, Z i.e. benzyloxycarbonyl, cHx i.e. cyclohexyl, Dnp i.e. dinitrophenyl, Trt i.e. trityl, Mtt i.e. methyltrityl or Bzl, i.e. a functional group of the following formula 
b) For scheme 1, R represents an amino acid side chain as defined above
c) Ar and Arxe2x80x2 represent an aromatic pharmacophore linked to the amino acid using the corresponding acid (Arxe2x80x94CO2H), the corresponding benzoyl hydrazide (Arxe2x80x2xe2x80x94CONHNH2) or an aromatic amine (Arxe2x80x2xe2x80x94NH2), and the like.
The definition of PG, PGxe2x80x2, R, Ar and Arxe2x80x2 is also presented on scheme 1 (vide infra). 
Reagents: a) Coupling reaction with Arxe2x80x2xe2x80x94NH2; b) 1) Deprotection; 2) Coupling reaction with Arxe2x80x94CO2H; c) Deprotection.
PG or PGxe2x80x2: Protective groups, same or different selected from Boc, Fmoc, Bzl, Z. tBu, cHx, Dnp, Trt, Mtt chosen according to the amino add used. NB: PGxe2x80x2 is not necessary for some amino acids.
Arxe2x80x2xe2x80x94NH2 for derivatives type I, II and IV: Selected from benzylamine, dopamine, 2,5-dimethoxyaniline, 3-hydroxy4-methoxyaniline, thiazole-2-amine, 2-(2xe2x80x2-thiophenyl)ethylamine, and the like
Arxe2x80x2xe2x80x94CONHNH2 for derivatives type III: Selected from benzoyl hydrazide, salicylic hydrazide and the like
Arxe2x80x94CO2H for derivatives type I, II, III and IV: Selected from caffeic acid, dihydrocaffeic acid, 3,4-dihydroxybenzoic acid, 3,5-dihydroxynaphthalene-2-carboxylic acid, 4,8-dihydroxyquinoline-2-carboxylic acid, 2,4-dihydroxypyrimidine-5-carboxylic add, 2,5-dimethoxycinnamoic acid, 3,4-di-(4-fluorobenzyloxy)benzoic acid, 3,4-di-4-fluorobenzyloxy)caffeic acid, 5-fluoro-2-hydroxybenzoic acid, 5-fluoroindole-2-carboxylic acid, 2-fluoro-6-hydroxybenzoic acid, 3-hydroxy-4-nitrobenzoic acid, 4-hydroxy-3-nitrobenzoic acid, indole-2-acid, N-(4-fluorobenzyl)indole-2-carboxylic acid, N-(4-fluorobenzyl)pyrrole-2-carboxylic acid, 3-nitrocinnamoic acid, 4-nitrocinnamoic acid, pyrrole-2-carboxylic acid, trans-3-indole acrylic acid, 2,4,6-trihydroxybenzoic acid, 3,4,5-trihydroxybenzoic acid, 2-thiophene acetic acid, and the like
In accordance with Scheme 1, illustrated above, different pharmacophores may be attached to the amino acid via the C-terminal with the subsequent coupling of Arxe2x80x94CO2H taking place at a later stage after the removal of the amino blocking group. Thus, compound 1 (e.g. a Boc amino acid or other N-protected amino acid) is coupled with an aromatic amine (Arxe2x80x2xe2x80x94NH2) using EDC and HOBt as coupling reagents in DMF to obtain compound 2. Then, compound 2 is treated to remove the protecting or blocking group PG to obtain the free amine; for example, the removal of a Boc group may be performed by stirring compound 2 in a mixture of TFA and methylene chloride at room temperature for a short period of time. The resulting free amine may then be coupled with the appropriate aromatic acid (Arxe2x80x94CO2H) using the EDC/HOBt coupling conditions in DMF to obtain compound 3. If needed, compound 4 is obtained by deprotection of the protecting group PGxe2x80x2 present on the side chain of the amino acid using standard reaction conditions (T. W. Greene and P. G. M. Wuts, Protective groups in organic synthesis, Wiley-Interscience, 3rd Ed., 1999).
Scheme 2 illustrates an alternate method for the preparation of a derivative in accordance with the present invention:
Note:
a) For scheme 2, PG and PGxe2x80x2, as mentioned above, may be any suitable (known) independently removable protecting group for protecting the amine functional group and the amino acid side chain functional group, when necessary. PG and PGxe2x80x2 are defined as above for scheme 1. PGxe2x80x3 may be any suitable independently removable protecting group for protecting the carboxylic acid end of an amino acid. PGxe2x80x3 may, for example, be Bzl or tert-Butyl
b) For scheme 2, R, Arxe2x80x94CO2H, Arxe2x80x2xe2x80x94NH2 and Arxe2x80x2xe2x80x94CONHNH2 are defined as above for scheme 1
The second approach illustrated in scheme 2 below proceeds by linking different pharmacophores to the amino acid via the N-terminal first. Thus, compound 1 is treated so as to protect the carboxylic acid functional group by means of a suitable protecting group PGxe2x80x3; for example compound 1 may be a Boc-amino acid which is benzylated with benzyl bromide to yield compound 5 in the form of a benzyl ester using cesium carbonate in DMF according to the method of S.-S. Wang et al. (J. Org. Chem. vol 49 p. 1286 (1977)). Secondly, the amino protecting group PG is removed to provide a free amino functional group; for example the removal of the Boc group from compound 5 may be carried out by stirring in a mixture of TFA and methylene chloride (1:1 (v/v)). The resulting free amino group is coupled with an Arxe2x80x94CO2H with EDC and HOBt in DMF providing the desired coupled product compound 6. The latter is treated to remove the protecting group PGxe2x80x3 to yield a free carboxylic acid group; for example the benzyl protecting group PGxe2x80x3 may be removed by hydrogenolysis using 10% Pd/C as catalyst. Finally the free carboxylic acid intermediate is coupled with an aromatic amine (Arxe2x80x2xe2x80x94NH2) to provide the desired derivative, namely compound 3. If needed, compound 4 is obtained by deprotection of the protecting group PGxe2x80x2 present on the side chain of the amino acid using standard reaction conditions. 
Reagents: a) Protection; b) 1) Deprotection; 2) Coupling reaction with Arxe2x80x94CO2H; c) 1) Deprotection; 2) Coupling reaction with Arxe2x80x2xe2x80x94NH2; d) Deprotection.
PG, PGxe2x80x2 or PGxe2x80x3: Protective groups, same or different such as Boc, Fmoc, Bzl, Z, tBu, cHx, Dnp, Trt, Mtt chosen according to the amino acid used. NB: PGxe2x80x2 is not necessary for some amino acid.
Arxe2x80x94CO2H, Arxe2x80x2xe2x80x94NH2, Arxe2x80x94CONHNH2: See description in scheme 1.
Scheme 3 illustrates a method for the preparation of a benzylated derivative in accordance with the present invention:
Note:
a) For scheme 3, R is an amino acid side chain without functional group or bearing a functional group which does not need to be protected. R may, for example, be H, CH3xe2x80x94, (CH3)2CHxe2x80x94, (CH3)2CHCH2xe2x80x94, CH3CH2CH(CH3)xe2x80x94, C6H5CH2xe2x80x94, CH3SCH2CH2xe2x80x94
b) For scheme 3, Arxe2x80x94CO2H and Arxe2x80x2xe2x80x94NH2 are defined as above for scheme 1 
Reagents: a) (HO)nArxe2x80x94CO2H, HOBt, EDC, DMF, 60xc2x0 C., 4 h; b) 1) K2CO3, 4-F-PhCH2Br, acetone, 23xc2x0 C., 16 h; 2) TFA/CH2Cl2 (1:1), 23xc2x0 C., 4 h; c) Arxe2x80x2xe2x80x94NH2, DIPEA, HOBt, DMF, 23xc2x0 C., 2.5 h.
In scheme 3 illustrated above the starting amino acid tert-butyl ester (compound 7) is obtained commercially or synthesized by standard means. Thus, compound 7 is coupled with (HO)nArxe2x80x94CO2H using EDC and HOBt as coupling reagents in DMF to obtain compound 8. The resulting material is benzylated with 4-fluorobenzylbromide (or other benzyl halide) and potassium carbonate in acetone to yield the acid (compound 9) after deprotection of the tert-butyl protective group. The tert-butyl ester is deprotected in a mixture of TFA/CH2Cl2 (1:1) for 4 h. The final material is coupled with an aromatic amine (Arxe2x80x2xe2x80x94NH2) (or benzoyl hydrazide) using EDC and HOBt as coupling reagents in DMF to yield compound 10.
Scheme 4 illustrates in a generic fashion a method for the preparation of derivative containing the same moiety at Nxcex1 and Nxcfx89 of an amino acid in accordance with the present invention (see example 11 for a more specific example):
Note:
a) For scheme 4, R represents a nitrogen containing amino acid side chain. R may, for example, be H2NCH2CH2CH2CH2xe2x80x94, H2NCH2CH2CH2xe2x80x94, H2NCH2CH2CH2CH2CH2xe2x80x94
b) For scheme 4, two protective groups were used; Boc for the Nxcex1 amino group and Z for the Nxcfx89 amino group. 
Reagents: a) Arxe2x80x2xe2x80x94NH2, DIPEA, HOBt, EDC, DMF, 60xc2x0 C., 2.5 h; b) 1) H2, 10% Pd/C, CH3OH; 2) TFA/CH2Cl2 (1:1), 23xc2x0 C., 2.5 h; 3) ArCO2H, HOBt, EDC, DIPEA, DMF, 60xc2x0 C., 4 h.
In scheme 4, commercially available Nxcex1-tert-butoxycarbonyl-Nxcfx89-benzyloxycarbonyl amino acid is coupled with an aromatic amine (or benzoyl hydrazide) using HOBt, EDC, DIPEA, as coupling reagents in DMF to yield compound 12. Hydrogenolysis of the Z protective group using 10% Pd/C in methanol followed by deprotection of the Boc group by stirring in a mixture of TFA/CH2Cl2 (1:1 (v/v)) gave the free Nxcex1,Nxcfx89-diamine. The two amino groups were coupled with ArCO2H using HOBt, EDC, DIPEA as coupling reagents in DMF to give the desired Nxcex1,Nxcfx89-disubstituted product 13.
Scheme 5 illustrates the potential preparation of an anti-integrase derivative using a solid phase methodology in accordance with the present invention (see example 29). Any suitable solid phase substrate could be used in such preparation (K. Burgess, Solid phase organic synthesis, Wiley-Interscience, 2000).
This process allows the introduction of pharmacophores to the amino acid via the N-terminal function. This process is illustrated or examplified with an histidine derivative. Thus, on scheme 5, Nxcex1-(9-fluorenylmethoxycarbonyl)-Nxcfx84-trityl-L-histidine 15 is bound to a polystyrene 2-chlorotrityl resin 14 in a DMF suspension for a period of 16 h. The resulting component 16 contained 0.6 mmol of histidine derivative/500 mg of resin. At this stage, after removal of the Fmoc protective group, the resin can be treated with a variety of aromatic acids (Arxe2x80x94CO2H) to give component 17. Cleavage of the resin leads to histidine derivative 18 which can be further transformed into HIV integrase inhibitors upon addition of aromatic amine (Arxe2x80x2xe2x80x94NH2) (or benzoyl hydrazide) on the free C-terminal end of the molecule as described earlier. 
Reagents: a) Histidine derivative, DIPEA, DMF, 23xc2x0 C., 16 h; b) 1) 30% piperidine, DMF, 23xc2x0 C., 1 h; 2) Arxe2x80x94NH2, HOBt, EDC, DMF, 60xc2x0 C., 4 h; c) AcOH/Trifluoroethane/CH2Cl2 (1:1:8), 23xc2x0 C., 2 h.
Scheme 6 illustrates the preparation of non commercially available aromatic acids used for the synthesis of several HIV integrase inhibitors in accordance with the present invention (see example 89 and 93 below for a more specific description of a process for making such derivatives):
For scheme 6 a) pyrrole-2-carboxylic acid 19 is benzylated using cesium carbonate and 4-fluorobenzyl bromide in DMF at room temperature for 3 h to give 96% of compound 20. Saponification of 20 with KOH in methanol at 70xc2x0 C. for 2 h gave N-(4-fluorobenzyl)pyrrole-2-carboxylic acid 21 (89%). 
Reagents: a) Cs2CO3, 4-F-PhCH2Br, DMF, 23xc2x0 C., 16 h; b) KOH, MeOH, H2O, 70xc2x0 C., 2 h. 
Reagents: a) 1) MeOH, H2SO4; 2) NaH, 4-F-PhCH2Br, DMF, 23xc2x0 C., 16 h; b) KOH, MeOH, H2O, 70xc2x0 C., 2 h.
For scheme 6 b) indole-2-carboxylic acid 22 is treated in methanol in the presence of sulfuric acid to give the methyl ester intermediate which is immediately benzylated by treatment with sodium hydride and 4-fluorobenzyl bromide in DMF to give N-(4-fluorobenzyl)indole-2-methyl carboxylate 23. Saponification of 23 with KOH in methanol at 70xc2x0 C. for 2 h gave N-(4-fluorobenzyl)indole-2-carboxylic acid 24 (75%). carboxylate 23. Saponification of 23 with KOH in methanol at 70xc2x0 C. for 2 h gave N-(4-fluorobenzyl)indole-2-carboxylic acid 24 (75%).
The compounds listed in Table 1 to 4 (appearing after the examples) were prepared by following Scheme 1, 2, 3, 4 or 5. Each of the xe2x80x9cexample numbersxe2x80x9d designating each of the compounds listed in these tables, correspond to the respective example number presented in the experimental section (see examples below). The activities of the listed compounds are also listed in the same tables, i.e. demonstrating their potential usefulness. A list of these tables follows:
Table 1: Describes HIV integrase inhibitors formula IIxe2x80x2. Compounds no. 1 to 54
Table 2: Describes HIV integrase inhibitors formula IIIxe2x80x2Compounds no. 55 to 72
Table 3: Describes HIV integrase inhibitors formula IVxe2x80x2. Compounds no. 73 to 81
Table 4: Describes HIV integrase inhibitors formula Ixe2x80x2. Compounds no. 82 to 113
As can be appreciated by the skilled artisan, the above synthetic schemes are not intended to comprise a comprehensive list of all means by which the compounds described and claimed in this application may be synthesized. Further methods will be evident to those of ordinary skill in the art.
For the purpose of Table 1 to 4, the HIV-1 integrase inhibition assay was carried out following a known procedure (Burke, Jr. T. R. et al., J. Med. Chem. 38, 4171-4178 (1995)). A suitable radiolabeled duplex substrate corresponding to the U5 end of the HIV LTR was used.
The novel compounds of the present invention are excellent ligands for integrase, particularly HIV-1, and most likely HIV-2 and HTLV-1 integrase. Accordingly, these compounds are capable of targeting and inhibiting an early stage event in the replication, i.e. the integration of viral DNA into the human genome, thus preventing the replication of the virus.
In addition to their use in the prophylaxis or treatment of HIV infection, the compounds according to this invention may also be used as inhibitory or interruptive agents for other viruses which depend on integrases, similar to HIV integrases, for obligatory events in their life cycle. Such compounds inhibit the viral replication cycle by inhibiting integrase. Because integrase is essential for the production of mature virions, inhibition of that process effectively blocks the spread of virus by inhibiting the production and reproduction of infectious virions, particularly from acutely infected cells. The compounds of this invention advantageously inhibit enzymatic activity of integrase and inhibit the ability of integrase to catalyze the integration of the virus into the genome of human cells.
The compounds of this invention may be employed in a conventional manner for the treatment or prevention of infection by HIV and other viruses which depend on integrases for obligatory events in their life cycle. Such methods of treatment, their dosage levels and requirements may be selected by those of ordinary skill in the art from available methods and techniques. For example, a compound of this invention may be combined with a pharmaceutically acceptable adjuvant for administration to a virally infected patient in a pharmaceutically acceptable manner and in an amount effective to lessen the severity of the viral infection. Also, a compound of this invention may be combined with pharmaceutically acceptable adjuvants conventionally employed in vaccines and administered in prophylactically effective amounts to protect individuals over an extended period of time against viral infections, such as HIV infection. As such, the novel integrase inhibitors of this invention can be administered as agents for treating or preventing viral infections, including HIV infection, in a mammal. The compounds of this invention may be administered to a healthy or HIV-infected patient either as a single agent or in combination with other antiviral agents which interfere with the replication cycle of HIV. By administering the compounds of this invention with other antiviral agents which target different events in the viral replication cycle, the therapeutic effect of these compounds is potentiated. For instance, the co-administered antiviral agent can be one which targets early events in the life cycle of the virus, such as cell entry, reverse transcription and viral DNA integration into cellular DNA. Antiviral agents targeting such early life cycle events include, didanosine (ddI), zalcitabine (ddC), stavudine (d4T), zidovudine (AZT), polysulfated polysaccharides, sT4 (soluble CD4)xe2x80x94which blocks attachment or adsorption of the virus to host cellsxe2x80x94and other compounds which block binding of virus to CD4 receptors on CD4-bearing T-lymphocytes. Other retroviral reverse transcriptase inhibitors, such as derivatives of AZT, may also be co-administered with the compounds of this invention to provide therapeutic treatment for substantially reducing or eliminating viral infectivity and the symptoms associated therewith. Examples of other antiviral agents include ganciclovir, dideoxycytidine, trisodium phosphonoformiate, eflornithine, ribavirin, acyclovir, alpha interferon and trimenotrexate. Additionally, non-ribonucleoside inhibitors of reverse transcriptase, such as TIBO, nevirapine or delavirdine, may be used to potentiate the effect of the compounds of this invention, as may viral uncoating inhibitors, inhibitors of trans-activating proteins such as tat or rev, or inhibitors of the viral protease. These compounds may also be co-administered with other inhibitors of HIV integrase.
Combination therapies according to this invention exert a synergistic effect in inhibiting HIV replication because each component agent of the combination acts on a different site of HIV replication. The use of such combinations also advantageously reduces the dosage of a given conventional anti-retroviral agent that would be required for a desired therapeutic or prophylactic effect as compared to when that agent is administered as a monotherapy. These combinations may reduce or eliminate the side effects of conventional single anti-retroviral agent therapies while not interfering with the anti-retroviral activity of those agents. These combinations reduce potential of resistance to single agent therapies, while minimizing any associated toxicity. These combinations may also increase the efficacy of the conventional agent without increasing the associated toxicity. Preferred combination therapies include the administration of a compound of this invention with AZT, 3TC, ddI, ddC, d4T, combivir, ziagen, sustiva, nevirapine and delavirdine.
Alternatively, the compounds of this invention may also be co-administered with other HIV protease inhibitors such as saquinavir (from Roche), indinavir (from Merck), nelfinavir (from Agouron), ritonavir (from Abbott) and amprenavir (from Glaxo) to increase the effect of therapy or prophylaxis against various viral mutants or members of other HIV quasi species.
We prefer administering the compounds of this invention as single agents or in combination with retroviral reverse transcriptase inhibitors, such as derivatives of AZT or HIV aspartyl protease inhibitors. We believe that the co-administration of the compounds of this invention with retro viral reverse transcriptase inhibitors or HIV aspartyl protease inhibitors may exert a substantial synergistic effect, thereby preventing, substantially reducing, or completely eliminating viral infectivity and its associated symptoms.
The compounds of this invention can also be administered in combination with immunomodulators (e.g., bropirimine, anti-human alpha interferon antibody, IL-2, GM-CSF, methionine enkephalin, interferon alpha, diethyldithiocarbante, tumor necrosis factor, naltrexone and rEPO); antibiotics (e.g., pentamidine isethionate) or vaccines to prevent or combat infection and disease associated with HIV infection, such as AIDS and ARC.
When the compounds of this invention are administered in combination therapies with other agents, they may be administered sequentially or concurrently to the patient. Alternatively, pharmaceutical or prophylactic compositions according to this invention may be comprised of a combination of an integrase inhibitor of this invention and another therapeutic or prophylactic agent.
Although this invention focuses on the use of the compounds disclosed herein for preventing and treating HIV infection, the compounds of this invention can also be used as inhibitory agents for other viruses that depend on similar integrases for obligatory events in their life cycle. These viruses include, but are not limited to, other diseases caused by retroviruses, such as simian immunodeficiency viruses, HTLV-I and HTLV-II.
Pharmaceutical compositions of this invention comprise any of the compounds of the present invention, and pharmaceutically acceptable salts thereof, with any pharmaceutically acceptable carrier, adjuvant or vehicle. Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethyleneglycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
The pharmaceutical compositions of this invention may be administered orally, parenterally by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. We prefer oral administration or administration by injection. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically acceptable carriers, adjuvants or vehicles. The term xe2x80x9cparenteralxe2x80x9d as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer""s solution and isotonic sodium chloride solutions. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as Ph. Helv. or a similar alcohol.
The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspension and solutions. In the case of tablets for oral administration carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
The pharmaceutical compositions of this invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycols.
Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application. For application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable neat formulation. Topically-transdermal patches are also included in this invention.
The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
Dosage levels of between about 0.01 and about 25 mg/kg body weight per day, preferably between about 0.5 and about 25 mg/kg body weight per day of the active ingredient compound are useful in the prevention and treatment of viral infection, including HIV infection. Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 5 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the patient treated and the particular mode of administration. A typical preparation will contain from about 5% to about 75% active compound (w/w). Preferably, such preparations contain from about 20% to about 50% active compound.
Upon improvement of a patient""s condition, a maintenance dose of a compound, composition or combination of this invention may be administered if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained. When the symptoms have been alleviated to the desired level, treatment should cease, at least in principle. Patients may, however, require intermittent treatment on a long-term basis, upon any recurrence of disease symptoms, especially for AIDS.
As the skilled artisan will appreciate, lower or higher doses than those recited above may be required. Specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the infection, the patient""s disposition to the infection and the judgment of the treating physician.
The compounds of this invention are also useful as commercial reagents which effectively bind to integrases, particularly HIV integrase. As commercial reagent, the compounds of this invention, and their derivatives, may be used to block integration of a target DNA molecule by integrase, or may be derivatized to bind to a stable resin as a tethered substrate for affinity chromatography applications. These and other uses which characterize commercial integrase inhibitors will be evident to those of ordinary skill in the art.
In the description herein, the following abbreviations are used:
Also, in alphabetical order, the following standard abbreviations were used for the description of the amino acids found in tables 1 to 4.
Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds.
The term stable, as used herein, refers to compounds which possess stability sufficient to allow manufacture and administration to a mammal by methods known in the art. Typically, such compounds are stable at a temperature of 40xc2x0 C. or less, in the absence of moisture or other chemically reactive conditions, for at least a week.